Unit 10 Haematologic, Hepatic and Renal Conditions

1. Unit 10 Haematologic, Hepatic and Renal Conditions

2. Learning Objectives • List causes of anaemia, low WBC counts, and platelet counts associated with HIV infection; • Describe treatment for the common causes of HIV-associated haematologic conditions, and; • Describe the evaluation of liver and kidney dysfunction. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

3. Blood Disorders Training on Clinical Care of HIV, AIDS and Opportunistic Infections

4. Case Study • Maggie, a 23 year old woman from Oshakati was diagnosed with HIV during her recent pregnancy. She and her baby each received a dose of nevirapine according to national guidelines. • She is seen now, 2 months after the birth, to be assessed for HAART. Maggie reports little energy. When she carries her baby and other heavy items she is breathless and aware of her heart pounding. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

5. Case Study (2) • Maggie has no fever, no night sweats, and no cough • She is not on any medication Training on Clinical Care of HIV, AIDS and Opportunistic Infections

6. Case Study: On Exam (3) • T 37.5°C, Pulse 110, RR 24, BP 110/60 • Pale mucous membranes & hand creases • No jaundice • No jugular venous distention • 2/6 systolic ejection murmur • Chest clear • No hepatosplenomegaly • No peripheral edema Training on Clinical Care of HIV, AIDS and Opportunistic Infections

7. Case Study: On Exam (4) • Hemoglobin 7.5 g/dl • MCV 75 • Reticulocyte count 0.3% • White Blood Count 3,600 • Platelet count 210,000 • Creatinine normal • ALT normal • RPR negative • Hepatitis B surface antigen negative • CD4 lymphocyte count 110 cells/cu mm Training on Clinical Care of HIV, AIDS and Opportunistic Infections

8. Degree of Anaemia • Mild anaemia • Hb > 10 g/dl to normal • Moderate anaemia • Hb 5 -10 g/dl • Severe anaemia • Hb < 5 g/dl Training on Clinical Care of HIV, AIDS and Opportunistic Infections

9. Mild Anaemia • Screen and investigate if: • Bleeding • Jaundice • Fever • Supportive treatment • Re-enforce counselling on good nutrition • Nutritional support with daily multivitamin/multimineral supplement • Reassess for response in 1-2 months Training on Clinical Care of HIV, AIDS and Opportunistic Infections

10. Moderate - Severe Anaemia • Evaluate for severity and a specific cause • History and physical • Acute or chronic blood loss • Chronic cough • Weight loss • Tachycardia, breathlessness, fatigue • Fever • Jaundice • Lymphadenopathy • Hepatosplenomegaly • Liver or kidney disease Training on Clinical Care of HIV, AIDS and Opportunistic Infections

11. Laboratory Evaluation • Laboratory testing may include: • FBC with RBC indices, reticulocytes • HIV test (if not done already) • In appropriate geographic regions • Malaria smear • Stool for ova and parasites (hookworm) • Urine for Schistosoma eggs • Chronic cough, fever or suspicion of TB • Sputum for direct microscopy • Chest x-ray if smears for AFB negative Training on Clinical Care of HIV, AIDS and Opportunistic Infections

12. Laboratory Evaluation (2) • If liver or kidney disease suspected • ALT / AST • Urea or creatinine • Suspected ulcer disease in older patients with iron deficiency • Stool for occult blood • Consider tests for • Serum Iron / ferritin / TIBC • Serum Folate • Serum B12 levels Training on Clinical Care of HIV, AIDS and Opportunistic Infections

13. Severe Anaemia • In case of a negative initial evaluation of severe anaemia: • Transfuse (if needed) after blood specimens obtained • Bone marrow aspirate or biopsy • TB or MOTT • Disseminated fungal infection • Malignancy • Other bone marrow condition Training on Clinical Care of HIV, AIDS and Opportunistic Infections

14. Anaemia Classification With Examples RBC Size Process Loss or Destruction (high retics) Inadequate Production (low retics) Microcytic (MCV < 80) chronic blood loss iron deficiency, chronic disease Normal size acute bleeding, haemolysis anaemia of chronic disease Macrocytic (MCV > 100) haemolysis B12, folate deficiency Training on Clinical Care of HIV, AIDS and Opportunistic Infections

15. Case Study: How would you Classify Maggie’s Anaemia So Far? • Moderate (Hb=7.5 g/dl, so between 5 and 10) • Microcytic (MCV=75, so <80) • Low reticulocyte count • Could be: • iron deficiency – multiple causes • anaemia of chronic disease (nb: no indication from initial investigations) Training on Clinical Care of HIV, AIDS and Opportunistic Infections

16. Microcytic Anaemia • Chronic iron loss • Normal menstruation • Pregnancy • Hookworm • Schistosomiasis • Non-infectious GI tract bleeding • Ulcer, gastritis, colon cancer • Anaemia of Chronic Disease • Nutritional deficiency • Thalassaemia • Congenital due to abnormal Hb synthesis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

17. Comparison of Iron-deficiency and Anaemia of Chronic Disease Training on Clinical Care of HIV, AIDS and Opportunistic Infections

18. Normocytic Anaemia • haemolysis – (before response activated) • Malaria • Autoimmune hemolytic anaemia • Early iron deficiency anaemia • Chronic renal failure • Decreased erythropoietin causes decreased RBC production • Chronic liver disease • Endocrine disorders • Bone marrow disorders Training on Clinical Care of HIV, AIDS and Opportunistic Infections

19. Normocytic Anaemia (2) • Anaemia of Chronic Disease • Reduced iron utilization for hemoglobin production despite adequate iron stores • Chronic infections • Advanced HIV • TB and MOTT • Chronic inflammatory disease • Rheumatoid arthritis • Collagen-vascular disease • Malignancy Training on Clinical Care of HIV, AIDS and Opportunistic Infections

20. Macrocytic Anaemia • haemolysis • Young RBCs are large • Malaria • Autoimmune hemolytic anaemia • Folate or B12 deficiency • Bone marrow disorders • Aplastic anaemia • Myelodysplastic syndrome • Some leukaemias Note: AZT and d4T cause macrocytosis. If there is no anemia, it does not need to be evaluated. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

21. HIV-Associated Anaemia • Anaemia is: • the most frequent haematological abnormality seen in patients with HIV • an independent predictor of all-cause mortality and AIDS-related mortality; also associated with a more rapid decline in CD4 counts* • often multifactorial in HIV patients *study in women with HIV in Tanzania:J. Acquir Immune Defic Syndr 2005;40:219-225 Training on Clinical Care of HIV, AIDS and Opportunistic Infections

22. HIV-Associated Anaemia (2) • Nutritional deficiencies complicated by malabsorption • Iron, Folate, B12 (?) • Protein • Anaemia of chronic disease • HIV, OIs, Malignancies • Reduced erythropoietin production • Disordered iron utilization • Cytokine production decreases marrow output Training on Clinical Care of HIV, AIDS and Opportunistic Infections

23. HIV-Associated Anaemia (3) • Specific OI • Parvovirus B19 • Marrow invasion • MOTT, TB, CMV, EBV, Lymphoma • Medications • Reduced production • AZT, (d4T) • Amphotericin • Trimethoprim, pyrimethamine • albendazole • haemolysis in G6PD deficiency (Sulfa, dapsone) Training on Clinical Care of HIV, AIDS and Opportunistic Infections

24. Case Study (5) • Factors likely to contribute to Maggie’s anaemia • Pregnancy • Reduced iron stores • Possible reduced folate • Intra –partum or post-partum bleeding • Possible role of parasitic infection • Malaria during pregnancy • Hookworm • Advanced immunosuppression • CD4 110 • Mild leucopoenia Training on Clinical Care of HIV, AIDS and Opportunistic Infections

25. Case Study: Maggie’s Lab Test Results • Malaria smear: negative • Stool parasite exam • Positive for hookworm • Measuring serum iron and folate may be useful if available • Iron low, RDW high, serum ferritin low • Folate normal Training on Clinical Care of HIV, AIDS and Opportunistic Infections

26. Case Study: Treatment • Maggie is treated for her hookworm with albendazole • She receives supplemental iron & folate • She begins OI prophylaxis with cotrimoxazole 960 mg daily • She begins isoniazid preventive therapy • She begins first line HAART with stavudine, lamivudine and nevirapine NB: treating HIV patients with iron in the absence of iron deficiency is not recommended Training on Clinical Care of HIV, AIDS and Opportunistic Infections

27. Case Study: Follow-up • After 3 months of combined therapy, Maggie’s haemoglobin is 11 grams/dl Training on Clinical Care of HIV, AIDS and Opportunistic Infections

28. Summary: Management of Anaemia In Patients with HIV • Classify the type of anaemia • Correct the cause of the anaemia • If iron deficiency, give iron after correcting the underlying problem • Give HAART if anaemia is due to HIV • Unexplained anaemia <8 g/dl is a WHO Clinical Stage 3 condition • Avoid AZT Training on Clinical Care of HIV, AIDS and Opportunistic Infections

29. HIV-Associated Leukopaenia and Neutropaenia • Common with advanced immunosuppression • Direct bone marrow suppression in advanced HIV disease • CMV, EBV, parvovirus B19 • Hypersplenism (TB, MAC) • Low lymphocyte count reflects reduction in CD4 cells • Drug toxicity a common cause of leukopaenia • Zidovudine, tenofovir • Sulfa, trimethoprim, pyrimethamine • Ganciclovir • 20-34% of HIV-infected will experience neutropaenia • Unexplained neutropaenia < 0.5 x 109/L is a WHO Clinical Stage 3 condition Training on Clinical Care of HIV, AIDS and Opportunistic Infections

30. Thrombocytopenia • About 11% of HIV-infected patients will develop a low platelet count (<100,000) • Up to 25-45% with advanced immunosuppression • May be part of marrow suppression in advanced HIV with anaemia and leukopaenia • Autoimmune • Immune thrombocytopenic purpura (ITP) • With haemolysis • Malaria • Thrombotic thrombocytopenic purpura (TTP) • Disseminated intravascular coagulation (DIC) • Drug toxicity: Ganciclovir, Ranitidine • Viral: Parvovirus B19 Training on Clinical Care of HIV, AIDS and Opportunistic Infections

31. Immune Thrombocytopaenic Purpura (ITP) • Antibodies against platelets or megakaryocytes • Bone marrow aspirate / trephine may help with diagnosis • Monitor platelet counts closely if >75,000 • If <75,000 (certainly < 20,000) and spontaneous bleeding consider treating: • HAART if proven ITP • Unexplained chronic platelets <50,000 is WHO Stage 3 • Avoid AZT – marrow suppressive • If does not remit, consider prednisone 30-60 mg/day • Intravenous immune globulin (IVIG) if available • Platelet transfusions in emergencies; most transfused platelets will be destroyed so this is not a lasting solution Training on Clinical Care of HIV, AIDS and Opportunistic Infections

32. Thrombotic Thrombocytopenic Purpura (TTP) • Rare but more common in HIV infected than in non-HIV infected • Disseminated platelet aggregation • Syndrome • Haemolytic anemia • Thrombocytopenia (thrombotic microangiopathy) • Fever • Acute renal failure • Altered mental status • Many precipitating factors • HIV infection • Pregnancy • Medications • Bacterial toxins Training on Clinical Care of HIV, AIDS and Opportunistic Infections

33. Thrombotic Thrombocytopenic Purpura (TTP) (2) Treatment • HAART • Support with platelet-depleted FFP for up to 3 weeks • Avoid platelet transfusions – may increase thrombotic risk • Corticosteroids • Consider splenectomy if refractory • Daily plasmapheresis • Not currently available in Namibia • Vincristine for relapse Training on Clinical Care of HIV, AIDS and Opportunistic Infections

34. Liver Disease Training on Clinical Care of HIV, AIDS and Opportunistic Infections

35. Patterns of Liver Abnormalities • Haemolysis/Indirect Bilirubin • Acute hepatocellular necrosis • Chronic hepatocellular disorders • Alcoholic hepatitis & cirrhosis • Infiltrative Disease • Cholestasis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

36. Liver Function Tests As An Aid In diagnosis See Handout 11.1 Training on Clinical Care of HIV, AIDS and Opportunistic Infections

37. Case 1 • 45 year old man presents to the clinic with jaundice, abdominal complaints and feeling “unwell”. He is HIV positive and has a CD4 count of 180. • Laboratory test results: • Elevated direct > indirect bilirubin • AST=360 U/L, ALT=180 U/L • GGT=235 U/L • Alkaline phosphatase normal • Albumin = 25 g/L • PT prolonged Training on Clinical Care of HIV, AIDS and Opportunistic Infections

38. Case 1 (2) • What is the most likely cause of his jaundice? • Alcoholic hepatitis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

39. Case 2 • 28 year old woman on HAART (d4T/3TC/NVP) presents very unwell with jaundice, high fever (39°C) and right-sided abdominal pain. • Laboratory test results: • Elevated direct > indirect bilirubin • AST=405 U/L, ALT=650 U/L • GGT=normal • Alkaline phosphatase = 200 U/L • Albumin = normal • PT normal Training on Clinical Care of HIV, AIDS and Opportunistic Infections

40. Case 2 (2) • What is the most likely diagnosis? • Acute hepatocellular necrosis, probably infectious in origin (fever) • What is the role of nevirapine in this case? Training on Clinical Care of HIV, AIDS and Opportunistic Infections

41. Case 3 • 36 year old woman on HAART presents with vague abdominal complaints. On examination she has hepatomegaly. • Laboratory test results: • Bilirubin normal • AST and ALT normal • GGT=100 U/L • Alkaline phosphatase = 300 U/L • Albumin normal • PT normal Training on Clinical Care of HIV, AIDS and Opportunistic Infections

42. Case 3 (2) • What pattern of liver injury does this probably represent? • Infiltrative Disease Training on Clinical Care of HIV, AIDS and Opportunistic Infections

43. Case 4 • 25 year old man with malaise, fever and jaundice. • Laboratory test results: • Indirect bilirubin high • AST = 65 U/L, ALT normal • All other liver tests normal Training on Clinical Care of HIV, AIDS and Opportunistic Infections

44. Case 4 (2) • What is the most likely explanation for the jaundice? • Haemolysis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

45. Case 5 • 48 year old man with jaundice which he first noticed a few weeks ago. • Laboratory test results: • Elevated direct > indirect bilirubin • AST=240 U/L, ALT=215 U/L • GGT=normal • Alkaline phosphatase = 200 U/L • Albumin = 26 g/L • PT mildly prolonged Training on Clinical Care of HIV, AIDS and Opportunistic Infections

46. Case 5 (2) • What could be the cause of his jaundice? • Chronic hepatocellular disorders Training on Clinical Care of HIV, AIDS and Opportunistic Infections

47. Case 6 • 30 year old man with jaundice, fever, and right upper quadrant pain. He has HIV and his CD4 count is 24. • Laboratory test results: • Elevated direct bilirubin • AST=230 U/L, ALT=250 U/L • GGT=115 U/L • Alkaline phosphatase = 400 U/L • Albumin = normal • PT normal Training on Clinical Care of HIV, AIDS and Opportunistic Infections

48. Case 6 (2) • What could be the cause of his jaundice? • Cholestasis • cholangitis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

49. Cholestasis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

50. Renal Disorders Training on Clinical Care of HIV, AIDS and Opportunistic Infections